There is strong evidence that a combination of genotypes, endogenous physiology, and exogenous exposures influence melanoma risk. However, the interaction of these factors in melanoma etiology remains unclear. In particular, inherited genotypes involved in response to environmental exposures (e.g., UV sun exposure) may modify an individual's risk of developing melanoma. Knowledge about interactions of these factors in melanoma etiology may improve the ability to identify individuals at increased melanoma risk. This knowledge may in turn be used to target individuals for primary or secondary melanoma prevention strategies. We propose a case-control study that will directly address the complex, multifactorial etiology of melanoma that involves the interaction of genotypes and other risk factors. This study will address a number of specific hypotheses. First, we will evaluate whether candidate susceptibility genotypes are associated with melanoma in a case-control analysis. Second, we will evaluate whether genotypes and other risk factors interact in melanoma etiology, and whether knowledge of genotypes will improve our understanding of melanoma etiology once other risk factors (e.g., dysplastic nevi, UV sun exposure, hair/eye color) are known. Third, we will evaluate whether genotypes and other exposures distinguish individuals with dysplastic nevi who do and do not eventually develop invasive melanoma. In order to address these hypotheses, we will undertake a study using the extensive resources of the pigmented Lesion Group at the University of Pennsylvania. The sample will consist of 400 melanoma cases with dysplastic nevi, 400 melanoma cases without dysplastic nevi, 400 subjects with dysplastic nevi but no history of melanoma, and 400 controls. Risk factor information will be obtained by questionnaire, a DNA biosample will be collected using a non-invasive cheek swab method, and diagnostic pathology information will be collected using a systematic approach. Analyses will be undertaken to evaluate the role of candidate genotypes and other risk factors in melanoma etiology, including genotype by environment interactions.